Process for the production of cyclopentene intermediate and intermediates obtained therefrom

ABSTRACT

A novel acid-catalysed rearrangement process to convert 7substituted-1-oxabicyclo(3,2,1)octane derivatives to 4 Beta substituted-1,2,3,3a Alpha ,4,6a Beta -hexahydro-2-oxo-1oxapentalene derivatives, which are useful intermediates, some of them novel, for the manufacture of prostaglandins, and prostaglandin-like compounds, of the A-series and 11-desoxy series.

United States Patent 1 Brown et al.

[ Jan. 21, 1974 1 PROCESS FOR THE PRODUCTION OF CYCLOPENTENEINTERMEDIATE AND INTERMEDIATEs OBTAINED THEREFROM 21 Appl. No.: 355,734

[30] Foreign Application Priority Data May 10, 1972 Great Britain21798/72 [52] US. Cl. 260/240 R, 424/305, 260/468 D,

260/586 R, 260/598, 260/611 R [51] Int. Cl C07d 5/06 [58] Field ofSearch 260/3433, 240 PG [56] References Cited UNITED STATES PATENTS12/1973 Brown et al. 260/3433 OTHER PUBLICATIONS Meinwald m 111., J. Am.Chem. Soc, vol. 80, pp. 6303 to 6305 (1958). Crabbe et al., TetrahedronLetters, No. 2, pp. 115-117(1972).

Corey et al., Tetrahedron Letters, NO. 2, pp. 1 l ll 13 (1972).

Corey et al., Tetrahedron Letters, No. 2, pp. 107 to 109 (1972).

Taub et al., Chem.. Commun., 1970, p. 1258 et seq.-

(copy unavailable in POSL, relied upon as abstracted by Axen et al.,infra.) On order from Lib. of Congress. Axen et al., Synthesis ofNatural Products (Chapter on The Total Synthesis of Prostaglandins),pages 81, 92 to 94 and 142 (1973), (original copy in Patent Officecannot be located to determine exact date of the book-copies made fromcopies of part of book, i.e., pp. 81 to 142 in Op. 120, exact date to beascertained. however, subject matter in this book is based on 1970publication above to be obtained, therefore, applicable subject matteragainst the claims).

Primary Examiner-John D. Randolph Attorney, Agent, or Firm-Cushman,Darby &

Cushman [57] ABSTRACT A novel acid-catalysed rearrangement process toconvert 7-substituted-l-oxabicyclo[3,2,l]octane derivatives to4B-substituted-l,2,3,3aa,4,6aB-hexahydro-2- oxo-l-oxapentalenederivatives, which are useful intermediates, some of them novel, for themanufacture of prostaglandins, and prostaglandin-like compounds. of theA-series and 1 l-desoxy series.

6 Claims, No Drawings PROCESS FOR THE PRODUCTION OF CYCLOPENTENEINTERMEDIATE AND INTERMEDIATES OBTAINED THEREFROM This invention relatesto a novel process for use in the manufacture of prostaglandinderivatives, particularly of prostaglandins and prostaglandin-likecompounds of the A-series, and of the ll-desoxy series; and to novelcyclopentene intermediates produced by said process.

Thus, according to the invention there is provided a process for theproduction of cyclopentene intermedi ates of the formula:

ment of an oxa bicyclo-octene derivative of the formula:

wherein R has the meaning stated above, by reaction thereof with anacid.

A suitable value for R when it is a protected hydroxymethyl radical is,for example, an alkanoyloxymethyl radical of 2 to 8 carbon atoms, forexample the acetoxymethyl radical, or an a-phenylalkoxymethyl radical'of8 t0-l2 carbon atoms, for example a benzyloxymethyl radical. A suitablevalue for R when it is a protected formyl radical is, for example, aformyl group protected as an acetal, for example a dialkoxymethylradical of 3 to 8 carbon atoms, for example the dimethoxymethyl radical.A suitable value for R when it is a protected 3-hydroxy-l-trans-alkenylradical is, for example, a 3-alkanoyloxy-l-trans-alkenyl radical whereinthe alkanoyl group contains 1 to 4 carbon atoms, for example the3-acetoxy-l-trans-octenyl or 3-acetoxy-l-trans-decenyl radical, or R isa 3- (tetrahydropyran-Z-yloxy)-l-trans-alkenyl radical, for example the3-(tetrahydropyran-2-yloxy)-l-transoctenyl or3-(tetrahydropyran-2-yloxy)-l-transdecenyl radical.

The rearrangement of the bicycloheptene derivative of the formula II maybe carried out in the presence of a strong acid, for example aninorganic acid, for example hydrochloric acid or sulphuric acid, or anorganic acid, for example an alkanesulphonic acid of l to 6 carbonatoms, for example methanesulphonic acid, or an arenesulphonic acid of 6to 10 carbon atoms, for example toluene-p-sulphonic acid, by mixing theacid and the bicycloheptene derivative in an inert solvent, for examplebenzene or toluene, at ambient temperature or at an elevatedtemperature, for example the reflux temperature of the solvent, for upto 25 hours.

The starting material of the formula II wherein R is a protectedhydroxymethyl radical may be obtained by reacting a S-(protectedhydroxymethyl)cyclopenta- 1,3-diene (III), for example5-benzyloxymethylcyclopenta-l,3-diene (III, R benzyl) or 5-(loweralkanoylmethyl) cyclopenta-l,3-diene, with an acrylic acid derivative(IV), for example 2-chloroacryloyl chloride (IV, R chlorine, Rchoroformyl), in a Diels-Alder reaction to give a bicycloheptenederivative V. The bicycloheptene derivative V is then hydrolysed to aketone VI, which is oxidised in a Baeyer Villiger reaction to therequired oxa-bicyclooctene VII (II, R protected hydroxymethyl).

The starting material of the formula II wherein R is a protected formylradical may be obtained by reacting for example a-acetoxyfulvene (VIII)in a Diels-Alder reaction with an acrylic acid derivative (IV), forexample 2-chloroacryloyl chloride (IV, R chlorine, R chloroformyl),Z-chloroacrylo-nitrile or a lower alkyl ester of 2-chloroacrylic acid,to give a bicycloheptene derivative IX, which is hydrolysed to give a5-anti*- carbaldehyde X. *antisignifies a substituent on the oppositeside of the C-7 bridge from the double bond.

'CH2OR2 R e a cH =cR R"- R III IV v J, R2OCH2 a oca a VI VII Theanti-carbaldehyde is isomerised by acid or in the presence of an amineto the corresponding syncarbaldehyde XI, and the formyl group isconverted to an acetal XII, for example the dimethyl acetal (XII, Rmethyl). Hydrolysis converts the groups R and R to the oxo radical of aketone XIII, Baeyer-Villiger oxidation of which gives the requiredstarting material XIV (II, R dimethoxymethyl).

The compounds of the formula II wherein R is a protected derivative of a3-hydroxy-l-trans-alkenyl derivative, which may be used as startingmaterial in the process of the invention, may be obtained by reaction ofa 7-syn-carbaldehyde of the formula XI with a phosphonate reagent of theformula (Cl-I ',O) PO.CI-I.COR (wherein R is a branchedor straightchainalkyl radical of 1 to 8 carbon atoms) to give a compound of the formulaXV. The ketone group is reduced with either zinc borohydride oraluminium tri-isopropoxide to the enol XVI, and the groups R and R arehydrolysed to the oxo group of the ketone XVII. The side-chain hydroxylis then protected, for example as a lower alkanoyl ester ortetrahydropyran-Z-yl ether, to give the required starting material XVIII(R lower alkanoyl or tetrahydropyran-Z-yl).

XIX

15 wherein R is an alkanoyloxymethyl radical of 4 to 8 carbon atoms, aprotected formyl radical or a protected CI'LOCOCII3 CILOCOCII3 I l N 9MR VIII OCH H- H CH0 5 5 (R 0) CH H (R O) CH H R XIII XII XIV

3-hydroxy-l-trans-alkenyl radical of 4 to 11 carbon atoms.

A suitable protected formyl radical, and a suitable protected3-hydroxy-l-trans-alkenyl radical are those defined above.

The compounds of the formula XIX may be converted to known intermediatesfor prostaglandins and prostaglandin-like compounds of the A series orthe l 1- desoxy series by conventional reactions known in the field ofprostaglandin chemistry.

Thus, for example, compounds of the formula XIX wherein R is analkanoyloxymethyl radical of 4 to 8 carbon atoms may be used in thesynthesis of A prostaglandins or prostaglandin-like compounds, in thesame way as the known compound I (R acetoxymethyl), from which Aprostaglandins are available directly.

prostaglandin-like compounds.

Thus, for example, the compound XIXa, (R dimethoxymethyl), the productdescribed in Example I hereafter, may be hydrolysed to give the aldehydeXX, which is reacted with a dimethyl 2-oxoalkylphosphonate, for exampledimethyl 2-oxoheptylphosphonate, in the presence of a strong base, togive the enone XXI. Reduction of the enone to the enol XXII with, forexxr R6COCH:CH H

6 R cH(oH).ca:cH H a cH(oH).cH:c H

m1 xvr R6CH(OR'7).CH:CH H

xvrrr The double bond in the cyclopentene ring of such compounds XIXmay, of course, be hydrogenated, or an earlier intermediate may behydrogenated, so as to lead, in the same way, toll-desoxy-prostaglandins or ample, di-isobornyloxy aluminiumisopropoxide, fol- 65 lowed by reaction of the enol with dihydropyran,gives the compound XIXb [R yloxy)-1-trans-octenyl].

3-(tetrahydropyran-2- XIXa /',\ /(CH2 COOH XXV 'IHPtetrahydropyran-2-yl.

The compound XIXb [R 3-(tetrahydropyran-2- yloxy)-l-trans-octenyl] maybe converted to prostaglandin A for example by reduction withdi-isobutyl aluminium hydride to the lactol XXIII which is reacted with(4-carboxybutyl) triphenylphosphonium bromide and n-butyl-lithium insulpholane to give the 9- hydroxyprostanoic acid derivative XXIV, andoxidation thereof with chromium trioxide in pyridine to the9-oxo-compound XXV, followed by hydrolysis of the tetrahydropyranylprotecting group gives prostaglandin 2- ln exactly the same way,l,2,3,3aB,4,6aB-hexahydro-2-oxo-4B-l3-(tetrahydropran-Z-yloxy)decl-trans-enylll-oxapcntalene,a homologue of compound XlXh, may be converted to ZO-ethylprostaglandinA The conversion of the compound I (R ymethyl) toll-desoxy-prostaglandin benzylox- E or to XXII O.THP

XXIII t 0, KS

" o oa Q CHO co. c n

H(ocH (and l5epiPGA ll-desoxy-prostaglandin F 04 is already known. Compounds XIX, also, may be converted in completely analogous manner toprostaglandins, or prostaglandinlike compounds, of the ll-desoxy series.

The invention is illustrated, but not limited, by the followingExamples:

EXAMPLE 1 8-Syn-dimethoxymethyl-3-0xo-2-oxabicyclo[3,2,1 oct-6-ene (mg)and toluene-p-sulphonic acid (50mg) were dissolved in dry benzene (7.5ml.). The solution was stirred at room temperature for 6 minutes, washedwith aqueous sodium bicarbonate solution and the organic phaseseparated. The organic extract was dried and the solvent was evaporatedunder reduced pressure to give 4B-dimethoxymethyl-l,2,3,3afi,4,6aflhexahydro-Z-oxo-l-oxapentalene (l, R dimethoio ymethyl)as an oil, R 0.28 (thin-layer chromatography on silica gel, developedwith 50% ether in benzene, the spots visualised by spraying the plateswith ceric sulphate solution, and subsequent heating). The n.m.r.spectrum in deuteriochloroform showed the following characteristicfeatures (5 values):

3.34, 6H, singlet, methoxy 4.10, 1H, doublet, CH(OCH 5.45, 1H,multiplet, C--6a proton 5.96, 2H, multiplet, C4, 5 olefinic protons The8-syn-dimethoxymethyl-3-oxo-2- oxabicyclo[3,2,l]-oct-6-ene used asstarting material may be obtained as follows:

Crude a-acetoxyfulvene (61g, 0.45mole) was dissolved in benzene (450ml., dried over 4A molecular sieves), and freshly distilled2-chloroacrylonitrile (235 g., 2.68 moles) and hydroquinone (250 mg.)were added. The resulting solution was heated under reflux for 21 hoursin an atmosphere of argon. The solvent was evaporated under reducedpressure to give a dark brown oil, which was purified by passage througha column of Florisil (1kg) using methylene chloride as eluant, to give7-acetoxymethylene-5- chlorobicyclo[2,2,llhept-2-ene-5-carbonitrile as apale yellow oil, R I 0.4 on thin layer chromatography on Merck silicagel plates, using methylenechloride as eluant. The n.m.r. spectrum ofthe product in deuteriochloroform showed the following features (8values):

1.7-2.9, 2H, complex, protons at C-6 2.08 and 2.09, 3H, complex, methylprotons 3.3-4.2, 2H, complex, bridgehead protons 6.1-6.7, 2H, complex,ring olefinic protons 6.81 and 6.82, 1H, complex, acetoxymethyleneolefinic proton 7'Acetoxymethylene5-chlorobicyclo[2,2,l ]hept-2-ene-S-carbonitrile, (35.8g.; 0.16.mole) was dissolved in dioxan (360ml,purified by passage through grade basic alumina, followed by purgingwith argon) and 2N hydrochloric acid (80ml.; 0.16 mole, purged withargon prior to use) was added, giving a pale yellow solution. Thesolution was further purged with argon for 30 minutes, and was thenheated in an oil bath, to maintain an internal temperature of 85C. i3C., for 4 days under an atmosphere of argon. The dioxan was evaporatedunder reduced pressure, and the residual liquid was basified withsaturated aqueous sodium bicarbonate. Water (200ml) and methylenechloride (120ml.) were added, and the resulting suspension was filteredthrough celite. The organic layer was separated, and the remainingaqueous solution was extracted with methylene chloride (4 X 50ml.). Theorganic layers were combined and dried, and the solvent was evaporatedunder reduced pressure. The residue was dried under high vacuum to give-chloro-7-synformylbicyclo[2,2,1]hept-2-ene-5-carbonitrile as a brownoil. The aldehyde mixture showed 2 spots having R 0.2 and 0.3respectively on thin layer chromatography on Merck 025mm. silica gelplates, using methylene chloride as eluant. The spots were detected byspraying the plates with ceric sulphate and then heating the plates. Then.m.r. spectrum in deuteriochloroform of the mixed aldehydes showed thefollowing features (8 values):

1.79 and 2.26, 1H, doublets, J=14Hz, endo hydrogen at C-6 2.48 and 2.84,1H, double doublets, J=14 and 61-12,

exo hydrogen at C-6 2.85 and 3.07, 1H, singlet, hydrogen at C7 3.42, 1H,broad singlet, bridgehead hydrogen 3.66 and 3.80, 1H, broad singlet,bridgehead hydrogen 6.06.6, 2H, complex multiplets, olefinic hydrogens9.50 and 9.57, 1H, doublets, J=1Hz, aldehyde hydro gen5-Chloro-7-syn-formylbicyclo[2,2,l lhept-2-ene-5- carbonitrile (l5g.,0.08mole), trimethyl orthoformate (26g, 0.25mole) andtoluene-p-sulphonic acid (710mg, 4mmoles) were dissolved in methanol(500ml.), and the solution was heated under reflux for 20 hours. Thesolvents were evaporated under reduced pressure and the residual oil wasdried under high vacuum using an oil pump, to give a mixture of epimeric5-chloro-7-syn-dimethoxymethylbicyclo[2,2,1]hept-2- ene-S-carbonitrile.

5-Chloro-7-syn-dimethoxymethylbicyclo[ 2,2, l ]hept-Z-ene-S-carbonitrile (45.5g.) was dissolved in ethanol (450ml)containing dimethyl sulphoxide (50ml, dried over 4A molecular sieves),sodium hydroxide (16.8g.) was added, and the solution was heated underreflux in an inert atmosphere for 20 hours. The solution was thencooled, diluted with water (500ml.) and extracted with methylenechloride (4 X 250ml.). The combined extracts were washed with water (4 X500ml.) and dried, and the solvent was removed under reduced pressure togive an oil, which on crystallisation from pentane gave the ketone7-syn-dimethoxymethyl 2- oxabicyclo[2,2,1]hept-5-ene, m.p. 45C., R =0.4(5% ethyl acetate in methylene chloride). The n.m.r. spectrum of theketone in deuteriochloroform showed'the following characteristicfeatures (8 values):

1.96, 2H, multiplet, Cl 1 .CO

2.52, 1H, doublet, C-7 proton 3.00, 1H, multi let 3.10. 1H, multiiilet}and Pmwns 3.24, 3H, singlet 3.30, 3H, singlet} methoxy 4.38, 1H,doublet, (CH O) .Cfl

5.98, 1H, multiplet 6.44, 1H, multiplet The ketone l 1 lg.) wasdissolved in methylene chloride l ml.) containing sodium bicarbonate(g), and m-chloroperbenzoic acid (125g) was added in portions to thestirred solution. The stirring was continued for 4 hours at roomtemperature, and the organic layer was washed successively withsaturated sodium sulphite solution, sodium bicarbonate solution andwater. The organic solution was dried, and the solvent was evaporatedunder reduced pressure to give 8-syndimethoxymethyl-3oxo-2-oxabicyclo[3,2, l ]oct-6-ene, R 0.3 (5% ethyl acetate in methylene chloride). Then.m.r. spectrum in deuteriochloroform showed the fol lowingcharacteristic features (8 values):

3.3, 6H, singlet, methoxy] groups 4.05, 1H, doublet, CH(OCH 5.00, 1H,broad singlet, C-l proton 6.2-6.9, 2H, multiplets, olefinic protonsEXAMPLE 2 The process described in Example 1 was repeated, using2-oxo-8-syn-[3-(tetrahydropyran-Z-yloxy)dec-1-trans-enyl].-l-oxabicyclo[3,2,1]oct-6-ene (25mg) in place ofthedimethoxy-methyl compound, 1.2mg. of toluene-p-sulphonic acid and3ml. of benzene, and heating the mixture under reflux for 19 hours, togive 1,2,3,3aB,4,6aB-hexahydro-2oxo 4B-l 3-(tetrahydropyran-Z-yloxy)dec-l-trans-enyl1- l oxapentalene (l, RB-(tetrahydropyran- 2-yloxy)- olefinic protons dec-l-trans-enyl), R 0.70and 0.75 (epimers at C-3 of the 4B-side chain) on thin-layerchromatography on silica gel eluted with 10% ethyl acetate in methylenedichloride The n.m.r. spectrum in deuteriochloroform showed thefollowing characteristic features (8 values):

0.90, 3H, triplet, methyl 4.64, 1H, multiplet, C-2 proton oftetrahydropyranyl group 5.08, 1H, multiplet, C-6a proton 5.50, 2H,multiplet, decenyl olefinic protons 5.95, 2H, multiplet, C- and C-6olefinic protons The2-oxo-8-syn-[3-tetrahydropyran-2-yloxy)dec-ltrans-enyl]-1-oxabicyclo[3,2,1]oct-6-eneused as starting material may be obtained as follows:

A solution of dimethyl 2-oxononylphosphonate (354mg, 1.4mmole) inanhydrous 1,2- dimethoxyethane (3.5ml.) at 78C. was treated withn-butyl-lithium (0.94ml. of a 1.32M solution in hexane), and the mixturewas stirred for minutes, to this mixture was added a solution of5-chloro-5- cyanobicyclo[ 2,2,1 lhept-2-ene-7-syn-carboxaldehyde (203mg.1.1 mmole) in 1.1-dimethoxyethane (2ml.). The reaction mixture was thenallowed to warm up to room temperature and after being stirred for 1hour was neutralised with glacial acetic acid. The solvents wereevaporated under reduced pressure, and the residue was chromatographedon Florisil, using methylene dichloride as eluant to yield5-chloro-5-cyano-7-syn-(3-oxodec-1-trans-enyl)-bicyclo[2,2,1]hept-Z-ene, R 0.3 (methylenedichloride). The n.m.r. spectrum in deuteriochloroform showed thefollowing characteristic features (8 values):

0.85, 3H, triplet, methyl group 1.55, 2H, broad triplet, -CO.CH C1i2.45, 2H, triplet, -COCH CH 6.10, 2H, doublet on multiplet, -Cfl.CO andC-3 olefinic proton 6.38, 1H, multiplet, C-2 olefinic proton 6.7, 1H,multiplet, CO-CH=C1 -1 A solution of the enone (102mg., 0.33mmole) andaluminum isopropoxidc (648mg, 3.3mmole) in benzcne/isopropanol(3:l)(8ml.) was heated in a bath at 80C. Solvent was allowed to distilfrom the mixture, and was continuously replaced with benzene/isopropanol(3:1). After 5 hours, the reaction mixture was cooled stirred withsaturated aqueous sodium hydrogen tartrate solution (ml.) for 10minutes, and diluted with brine/water (1:1) (5ml.). The mixture wasextracted with ethyl acetate (4 X 5ml.), the combined extracts weredried and the solvent was evaporated under reduced pressure to give theenol, 5-chloro-5-cyano-7-syn-(3-hydroxydec-1-trans-enyl)bicyclo-[2,2,1]hept- 2-ene, R,- 0.2(methylene dichloride). The n.m.r. spectrum in deuteriochloroform showedthe following characteristic features (8 values):

0.84, 3H, triplet, methyl 1.5-2.9, 2H, multiplet, C-6 protons 3.95, 1H,broad, C11(OH) 5.51, 2H, multiplet, -Cfl=CH .CH(O1-l)- 6.02, 1H, multilet,

6.32, 1H, multigleal O2 and Proms To a solution of the enol (243mg,0.179mmole) in dimethyl sulphoxide (2.4ml.) was added an aqueoussolution of potassium hydroxide (8.6N, 0.19ml., 1.7mmole), and theresulting mixture was stirred for 18 hours, in an inert atmosphere. Thereaction mixture was then diluted with water (5ml.) and extracted withether (4 X 5ml.). The combined extracts were washed with water (2 X3ml.) and dried, and the solvent was evaporated under reduced pressureto yield 7-syn-(3- hydroxydec- 1-trans-eny1)bicyclo[2,2,1]hept-2-en- 55-one, R 0.3 (10% ethyl acetate in methylene dichloride). The n.m.r.spectrum in deuteriochloroform showed the following characteristicfeatures (8 values):

0.87, 3H, triplet, methyl 2.00, 2H, multiplet, C-6 protons 3.99, 1H,multiplet, C(OH) 5.6, 2H, multiplet, Cl;l=C1 1 .CH(OH)- 5.90, 1H,multiplet, 6.41, 1H, quartet, lC-Z and C-3 protons The enol ketone(58mg, 0.22mmole) was dissolved in dry methylene dichloride lmc.)containing dihydropyran (0.1ml.). A solution of toluene-p-sulphonic acidin tetrahydrofuran (0.05ml. of 1.0% solution) was added, and the mixtureallowed to stand for 5 minutes. Pyridine (1 drop) was then addedfollowed by ethyl acetate (10ml.). The mixture was then washedsuccessively with saturated sodium bicarbonate solution and brine, andwas dried, and the solvents were evaporated under reduced pressure togive 7-syn-[32-yloxy)dec1- trans-enyl]-2-oxabicyclo[2,2,1]hept-S-ene, R0.3 and 0.4 (5% ethyl acetate in methylene dichloride). The n.m.r.spectrum in deuteriochloroform showed the following characteristicfeatures (8 values):

0.85, 3H, triplet, methyl 2.00, 2H, multiplet, C-3 protons 4.6, 1H,multiplet, C-2 proton of tetrahydropyranyl 5.2-5.7, 2H, multiplet,olefinic protons of 7-decenyl 5.9, 1H, multiplet 6.4, 1H, multiplet} C-5and C-6 olefinic protons The tetrahydropyranyl ether (60mg, 0.17mmole)was dissolved in methylene dichloride (3ml.) containing solid sodiumbicarbonate (29mg, 0.34mmole). The stirred mixture was cooled to 0C.,m-chloroperbenzoic acid (33mg, 0.18mmole) was added and the mixture wasstirred at (0C. for 3 days. Saturated sodium sulphite solution wasadded, the organic layer was separated and dried, and the solvent wasevaporated under reduced pressure to give 2-oxo-8-syn-[3-(tetrahydropyran-2-yloxy)-dec-1-trans-enyl]-1- oxabicyclo[3,2,l]oct-6-ene, R of epimers 0.3 and 0.4 (296% methanol in methylenedichloride). The n.m.r. spectrum showed the following characteristicfeatures (8 values):

5.85, 31-1, triplet, methyl 4.6, 1H, multiplet, C2 proton oftetrahydropyranyl 5.9-6.6, 4H, multiplet, olefinic protons.

EXAMPLE 3 4.52, 2H, singlet, PhCfi O- 55.5, ]H, multiplet, C6a/3 proton6.0, 2H, multiplet, olefinic protons 7.3, H, singlet, aromatic protonsEXAMPLE 4 4B-Dimethoxymethyl-l ,2,3,3aB,4,6a,8-hexahydro-2-oxo-l-oxapentalene (1.49g.) was stirred with 2N hydrochloric acid(18.6ml.) at room temperature for minutes. An excess of solid sodiumbicarbonate was added, followed by solid sodium chloride. The resultingsolid material was triturated thoroughly with ethyl acetate (5 X ml.)the combined organic solutions were dried, and the solvent wasevaporated under reduced pressure to yield 4B-formyl-l.2,3.3(xB.4,6aB-hexahydro-2-oxo-1-oxapentolene as an oil, R 0.1 (ether). The n.m.r.spectrum of the aldehyde in deuteriochloroform showed the followingcharacteristic features (5 values):

3.55, 1H, broad singlet, C4a proton 5.50, 1H, broad doublet, C6aB proton6.10, 2H, multiplet, olefinic protons 9.60, 1H, doublet, aldehyde protonA solution of dimethyl 2-oxoheptylphosphonate (2.16g.) in anhydrous1,2-dimethoxyethane (60ml.) at

78C. was treated with n-butyl-lithium (3.16ml. of 2.29M solution inhexane), the mixture was stirred for 10 minutes, and a solution of thecrude aldehyde (1.00g.) in 1,2-dimethoxyethane (20ml.) was added. Thereaction mixture was then allowed to warm up to room temperature, andafter 4 hours was neutralized with glacial acetic acid. The solventswere evaporated under reduced pressure and the residue was partitionedbetween methylene dichloride (100ml.) and brine (20ml.). The aqueouslayer was separated, extracted twice with methylene dichloride, thecombined organic extracts were dried, and the solvent was evaporatedunder reduced pressure. The residue was chromatographed on silica gel,and elution with 5% ethyl acetate in methylene dichloride gave theenone, 1,2,3,3aB,4,6- aB-hexahydro-2-oxo-4B-(3-oxooct-1-trans-eny1)-1-oxapentalene, R 0.8 (5% ethyl acetate in methylene dichloride). Then.m.r. spectrum in deuteriochloroform showed the followingcharacteristic features (8 values):

0.89, 3H, triplet, methyl 3.42, 111. broad doublet C-4a proton 5.56, 1H,broad doublet, C-6otfit proton 6.01, 211, singlet, C5 and C6 protons6.08, 1H, doublet, -CH:C1j.CO

6.66, 1H, quartet, -C1;1:CH.CO-

A solution of the enone (1.28g.) in toluene (50ml.) was treated with atoluene solution of di-isobornyloxy aluminium isopropoxide (40ml, 0323M)at room temperature for 2 hours. The solution was then diluted withethyl acetate (100ml) and stirred for a short time with a saturatedsolution of sodium hydrogen tartrate. The mixture was filtered, theorganic phase was separated and dried, the solvent was evaporated underreduced pressure and the residue was chromatographed on silica gel.Elution with ethyl acetate/methylene dichloride (75:25) gave the enol,1,2,3,3aB,4,6aB-hexahydro-4B-(3-hydroxyoct-1-trans-enyl)-2-oxo-l-oxapentalene as a mixture of epimersat C3 of the side chain, R,' 0.2 and 0.3 (5% ethyl acetate in methylenedichloride). The n.m.r. spectrum in deuteriochloroform showed thefollowing characteristic features (8 values):

0.85, 3H, triplet, methyl 1.84, 1H, singlet, hydroxy 3.23, 11-1, broad,C4a proton 4.05, 1H, broad, C.OH

5.52, 3H, multiplet, C-6ozB and side chain olefinic protons 5.95, 2H,multiplet, C5 and C6 protons To a solution of the epimeric enols (631mg)in anhydrous methylene dichloride (9.5ml.) under an atmosphere ofnitrogen, were added successively redistilled 2,3-dihydropyran (1.89ml.)and a solution of anhydrous toluene-p-sulphonic acid in tetrahydrofuran(0.16 ml. of a 1% solution). After 15 minutes, pyridine (3 drops) wasadded, followed by ethyl acetate (50ml.). The solution was washedsuccessively with saturated sodium bicarbonate solution and saturatedbrine, and was dried. Evaporation of the solvents under reduced pressuregave a mixture of the epimeric tetrahydropyranyl ethers of the enols, R0.8 (5% ethyl acetate in methylene dichloride). The n.m.r. spectrum indeuteriochloroform showed the following characteristic features (8values):

0.87, 3H, triplet, methyl 3.25, 1H, broad, C-4a proton 3.3-4.1, 31!,multiplet, C-O- 4.62, 1H, broad, C2 proton of tetrahydropyranyl 5.1-5.7,3H, multiplet, C6aB and side-chain olefinic protons.

5.95, 2H, multiplet, C-5 and C6 protons.

To a solution of the crude epimeric tetrahydropyranyl ethers (800mg) indry toluene (50ml.) under an atmosphere of argon at 78C. was added asolution of di-isobutyl aluminium hydride (1.47ml. of 1.96M solution intoluene). After 15 minutes, the reaction was quenched by dropwiseaddition of methanol (lml.) and after a further 15 minutes at roomtemperature a mixture of 1 :1 brine/water 10ml.) was added. The mixturewas extracted with ethyl acetate (3 X 10ml), the combined organicextracts were washedrwith brine and dried, and the solvents wereevaporated under reduced pressure to give an epimeric mixture oflactols, 1,2,3,3- 018,4,6aB-hexahydro-2-hydroxy-4B-(3-hydroxyoct1-trans-eny1)-l-oxapentalene as an oil R 0.5 (5% methanol in methylenedichloride). The n.m.r. spectrum in deuteriochloroform showed thefollowing characteristic features (6 values):

0.88, 3H, triplet, methyl 3.1, 1H, broad, C-4a proton 4.66, 1H, broad,C2 proton of tetrahydropyranyl 5.52, 21-1, multiplet, side-chainolefinic protons 5.76, 2H, multiplet, C5 and C6 protons.

Finely powdered (4-carboxybutyl)triphenylphosphoriium bromide (1.75g.)was heated to C. under vacuum for 1 hour. The evacuated vessel was thenfilled with dry nitrogen, and the solid was dissolved in warm anhydroussulpholane (20ml.). To this warm solution was added dropwisen-butyl-lithium (3.25ml. of a 2.29M solution in hexane) and the mixturewas stirred for 1 hour at room temperature. To this mixture was added asolution of the epimeric lactols (500mg) in a mixture of sulpholane(6ml.) and toluene (2ml.) and the solution was stirred at roomtemperature for 1 hour. Water (10ml.) was added, the mixture wasextracted with ether (4 X 10ml.), and the extracts were discarded. Theaqueous solution was then acidified to pH 3 with 2N aqueous oxalic acidand then extracted with a mixture of equal parts of ether and pentane (3X 50ml). The combined organic extracts were dried, the solvents wereevaporated under reduced pressure,

and residual sulpholane was removed by pumping under high vacuum. Theresidue was then chromato' graphed on silica gel, and elution with amixture of acetone and cyclohexane (20:80) gave the hydroxy acid,9oz-hydroxyl tetrahydropyran-Z-yloxy)-5-cis, l0,l3-trans-prostatrienoicacid, as an oil, R 0.3 methanol in methylene dichloride). The n.m.r.spectrum in deuteriochloroform showed the following characteristicfeatures (8 values):

0.90, 3H, triplet, methyl 3.05, 1H, broad, Cl2a proton 4.80, 1H, broad,C-2 proton of tetrahydropyranyl 5.3-6.0, 6H, multiplet, olefinicprotons.

A mixture of anhydrous methylene dichloride (86011.1), anhydrouspyridine (5Sp.l.) and chromium trioxide (34.3mg.) was stirred at roomtemperature under an atmosphere of argon for minutes. A solution of thehydroxy acid (24mg) in methylene dichloride (ZOO L) was added. and themixture was stirred for 15 minutes. The organic layer was decanted andthe residue was washed with ether (2 X 2 ml.). The combined organiclayers were washed successively with 1N hydrochloric acid (2ml.) andbrine (2 X 3 ml.), and dried, and the solvents were evaporated underreduced pressure. The residue was chromatographed on silica gel(Mallinckrodt CC4), and elution with a mixture of ether and pentane(1:1) gave the keto acid, 9-oxo-15- (tetrahydropyran-Z-yloxy)-5 -cis,10,13-transprostatrienoic acid, as an oil, R 0.3 (5% methanol inmethylene dichloride). The n.m.r. spectrum in deuteriochloroform showedthe following characteristic features (8 values):

0.89, 3H. triplet, methyl 3.26. 1H. broad, C-lZa proton 3.4-4.2, 3H.multiplet, C-1 5, and C-6 of tetrahydropyranyl. protons.

4.67, 1H, broad. C-2 of tetrahydropyranyl 5.42, 2H, multiplet,side-chain trans-olefinic protons 5.59, 2H, multiplet, cis-olefinicprotons 6.17, 1H, multiplet, Cll proton 7.48, 1H, multiplet, C-10 protonA mixture of the keto-acid (6.2mg.), acetic acid (240;;1.) and water(120;Ll.) was heated at 50C. for 1 hour under an atmosphere of nitrogen.The solvent was then evaporated under reduced pressure the residue wastaken up in ether, and the ether solution was washed with brine. Theseparated organic phase was dried, and the solvent was evaporated underreduced pressure to give the C-l5 epimers of l5-hydroxy-9-oxo-5-cis,10,13-transprostatrienoic acid. The epimers were separated bythin layer chromatography on silica gel using 1% acetic acid in ether asthe eluting solvent. The more polar spot, R 0.40, was a mixture ofcistrans epimers in the top side-chain, which were separated bychromatography on silver nitrate impregnated silica-gel. The transisomer was identical, except for optical activity, with authenticprostaglandin A The n.m.r. spectrum in hexadeuterio-acetone showed thefollowing characteristic features (8 values):

0.90, 3H, triplet, methyl 3.31, 11-1, multiplet, C-1 20: proton 4.05,1H, multiplet, C-l5 proton 5.45, 2H, multiplet, C-5 and C-6 protons5.64, 211, multiplet, C-1 3 and Cl4 protons 6.12, 1H, multiplet, C-llproton 7.59, 1H, double doublet, C-10 proton What we claim is: l. Aprocess for the production of cyclopentene intermediates of the formula:

wherein R is selected from the group consisting of dialkoxymethyl of 3to 8 carbon atoms and 3 (tetrahydropyran-Z-yloxy)-1-trans-a1kenylwherein the alkenyl part is of4 to l 1 carbon atoms, which intermediatesare useful for the manufacture of prostaglandins, or prostaglandin-likecompounds, of the A-series or of the ll-desoxy series, which comprisesreacting an oxabicyclo-octene of the formula:

wherein R has the meaning stated above, with an acid.

2. The processof claim 1 wherein in the starting material R isdimethoxymethyl, 3-( tetrahydiopyran-Z- y1oxy)-l-trans-octenyl or3-(tetrahydropyran-2-yloxy)- l-trans-decenyl.

3. The process of claim 1 wherein the acid is toluenep-sulphonic acid.

4. A cyclopentene derivative of the formula:

wherein R is selected from the group consisting of dialkoxymethyl of 3to 8 carbon atoms and 3- (tetrahydropyran2yloxy)-l-trans-alkenyl whereinthe alkenyl part is of 4 to 11 carbon atoms.

5. The cyclopentene derivative of claim 4 which is4B-dimethoxymethyl-l,2,3,3aB,4,6aB-hexahydro-2- oxo-l-oxapentalene.

6. The cyclopentene derivative of claim 4 which is 1,2',3,3aB,4,6aB-hexahydro-2-oxo-4B-13- (tetrahydropyran-Z-yloxy)oct-1-trans-enyll-1 oxapentalene or l,2,3,3aB,4,6aB-hexahydro-2-oxo4fl-[3-(tetrahydropyran-Z-yloxy)dec-1-trans-eny1]-loxapentalene.

2. The process of claim 1 wherein in the starting material R1 isdimethoxymethyl, 3-(tetrahydropyran-2-yloxy)-1-trans-octenyl or3-(tetrahydropyran-2-yloxy)-1-trans-decenyl.
 3. The process of claim 1wherein the acid is toluene-p-sulphonic acid.
 4. A cyclopentenederivative of the formula:
 5. The cyclopentene derivative of claim 4which is 4 Beta -dimethoxymethyl-1,2,3,3 Alpha Beta ,4,6 Alpha Beta-hexahydro-2-oxo-1-oxapentalene.
 6. The cyclopentene derivative of claim4 which is 1,2,3,3 Alpha Beta ,4,6 Alpha Beta -hexahydro-2-oxo-4 Beta-(3-(tetrahydropyran-2-yloxy)oct-1-trans-enyl)-1-oxapentalene or 1,2,3,3 Alpha Beta ,4,6 Alpha Beta -hexahydro-2-oxo-4 Beta-(3-(tetrahydropyran-2-yloxy)dec-1-trans-enyl)-1-oxapentalene.